Ultragenyx Pharmaceutical Inc (RARE) 2025 Q1 法說會逐字稿

Good afternoon, and welcome to the Ultragenyx first-quarter 2025 financial results conference call. (Operator Instructions)

下午好，歡迎參加 Ultragenyx 2025 年第一季財務業績電話會議。（操作員指示）

Now my pleasure to turn the call over to Joshua Higa, Vice President of Investor Relations.

現在我很高興將電話轉給投資者關係副總裁 Joshua Higa。

Thank you. We've issued a press release detailing our financial results, which you can find on our website at ultragenyx.com. Joining me on this call are Emil Kakkis, Chief Executive Officer and President; Erik Harris, Chief Commercial Officer; Howard Horn, Chief Financial Officer, and Eric Crombez, Chief Medical Officer.

謝謝。我們發布了一份新聞稿，詳細介紹了我們的財務業績，您可以在我們的網站 ultragenyx.com 上找到。參加本次電話會議的還有執行長兼總裁 Emil Kakkis；埃里克·哈里斯（Erik Harris），首席商務官；首席財務官 Howard Horn 和首席醫療官 Eric Crombez。

I'd like to remind everyone that during today's call will be making forward-looking statements. These statements are subject to certain risks and uncertainties. Our actual results may differ materially. Please refer to the risk factors discussed in our latest SEC filings.

我想提醒大家，今天的電話會議將會做出前瞻性的陳述。這些聲明受到一定風險和不確定性的影響。我們的實際結果可能會有重大差異。請參閱我們最新的 SEC 文件中討論的風險因素。

I'll now turn the call over to Emil.

我現在將電話轉給艾米爾。

Thanks, Josh, and good afternoon, everyone.

謝謝，喬希，大家下午好。

In the first quarter, we continued to make meaningful progress across one of the most productive commercial enrollment pipelines in rare diseases. Our commercial team delivered strong quarter that puts us in position to have another year with meaningful revenue growth.

在第一季度，我們繼續在罕見疾病領域最具成效的商業招募管道之一中取得有意義的進展。我們的商業團隊在本季度表現出色，這使我們能夠在來年實現有意義的收入成長。

Our early investments in high performing teams have helped generate substantial revenue growth while we commercialize our products outside of the United States.

我們早期對高績效團隊的投資幫助我們在美國以外地區實現產品商業化的同時實現了可觀的收入成長。

At the same time, we are preparing to launch our next set of programs in the US and around the world. Our development teams have advanced our large and late-stage programs as well. For the UX143 in osteogenesis imperfecta, patients in the Phase 3 phase have now been enrolled for at least a year, and the process begun to clean and lock the databases for our second interim analysis.

同時，我們正準備在美國和世界各地推出下一系列項目。我們的開發團隊也推進了我們的大型和後期專案。對於成骨不全症的 UX143，第 3 階段的患者現已入組至少一年，並且已開始清理和鎖定資料庫以進行我們的第二次中期分析。

For GTX102 in Angelman syndrome, the Phase 3 is enrolling efficiently at sites in the United States, Canada, Japan, Germany, Poland, and Spain, and data are expected in 2026. For DTX301 in ornithine transcarbamylase deficiency, or OTC, the Phase 3 study completed enrollment in the first quarter is on track to read out data over the next year. For UX701 Wilson disease, the study is now enrolling the fourth dose finding cohort that will enable dose selection and transition to the pivotal stage.

對於治療 Angelman 症候群的 GTX102，第 3 階段正在美國、加拿大、日本、德國、波蘭和西班牙的研究中心高效招募患者，預計 2026 年可以獲得數據。對於治療鳥氨酸轉氨甲酰酶缺乏症（OTC）的 DTX301，其第 3 階段研究已於第一季完成招募，預計明年讀取數據。對於 UX701 威爾遜氏症，該研究目前正在招募第四批劑量探索隊列，以便進行劑量選擇並過渡到關鍵階段。

At the same time, we're working on two separate BLAs: one currently under review and a second to be submitted. The DTX401 for GSDIa BLA submission is on track for mid-2025 after successfully completing the PPQ runs, the qualification loss essentially at our manufacturing facility in Bedford, Massachusetts.

同時，我們正在製定兩個獨立的 BLA：一個目前正在審核中，另一個即將提交。在成功完成 PPQ 運行後，DTX401 的 GSDIa BLA 提交預計在 2025 年中期完成，資格審查主要在我們位於馬薩諸塞州貝德福德的製造工廠進行。

The UX111 for Sanfilippo syndrome BLA under review by the FDA is progressing on schedule as expected. It's not our standard practice to go into the details of regular interactions, but think it's meaningful at this current time for investors to be aware that our interaction with the FDA on the UX111 BLA review thus far remain on track.

FDA正在審查的用於治療Sanfilippo綜合徵的UX111 BLA正在按預期按計劃進行。詳細說明定期互動並不是我們的標準做法，但我認為目前讓投資者知道我們與 FDA 就 UX111 BLA 審查的互動迄今為止仍在正常進行中是有意義的。

Last month, we had our mid-cycle review meeting that occurred on the standard timeline. We also know the inspections of the manufacturing facilities and clinical sites have been scheduled according to normal cadence and are currently underway. We remain on track for the PDUFA action date of August 18.

上個月，我們按照標準時間表召開了中期審查會議。我們也知道，對製造設施和臨床站點的檢查已經按照正常節奏安排，目前正在進行中。我們仍按計劃按時完成 8 月 18 日的 PDUFA 行動。

Going forward, we don't plan on giving the details of all our regulatory interactions, but we did want to share enough detail for you to remain confident as you are that the UX111 BLA review is progressing according to plan.

展望未來，我們不打算提供所有監管互動的細節，但我們確實希望分享足夠的細節，以便您確信 UX111 BLA 審查正在按計劃進行。

With that, I'll turn it over to rest of the team to share the details of why 2025 will be a transformational year for Ultragenyx. Eric, I'll hand it off to you to go through the commercial team's execution in the first quarter.

接下來，我將把主題交給團隊的其他成員，讓他們詳細解釋為什麼 2025 年將成為 Ultragenyx 的轉型之年。艾瑞克，我會把第一季商業團隊的執行情況交給你。

Thank you, Emil, and good afternoon, everyone. In the first quarter, the commercial organization continue building on the momentum that we saw at the end of 2024. Starting with Crysvita in Latin America, where we lead commercial operations, our team generated approximately 40 new start forms that led to approximately 40 patients on reimbursed therapy. We now have approximately 775 patients on commercial product in the region, as the team continues to exceed our expectations for Crysvita.

謝謝你，艾米爾，大家下午好。第一季度，商業組織繼續保持我們在 2024 年底看到的勢頭。從我們領導商業運營的拉丁美洲的 Crysvita 開始，我們的團隊生成了大約 40 份新的啟動表格，使大約 40 名患者獲得了報銷治療。目前，我們在該地區約有 775 名患者使用商業產品，因為該團隊對 Crysvita 的表現繼續超出我們的預期。

Physicians in the region consistently tell us how well their patients feel on therapy, which has led to an increasing number of doctors writing prescriptions for multiple patients. We expect growth in the region to continue following the successful negotiation of reimbursement from the Brazilian and Mexican authorities, which are the two largest payers in the region, and continued expansion in other Central and South American countries.

該地區的醫生不斷告訴我們他們的病人對治療的感覺如何，這導致越來越多的醫生為多名病人開處方。我們預計，在成功與該地區最大的兩個付款國巴西和墨西哥當局談判報銷協議，並繼續向其他中美洲和南美洲國家擴張之後，該地區的增長將繼續。

In the United States, our partner, Kyowa Kirin, is leading commercialization for Crysvita. The first quarter 2025 revenue was supported by increasing new start forms and new patients on reimbursed therapy. It is fulfilling to see that adults around adult demand -- it is fulfilling to see that adults around -- adults have exceeded the -- make up more than half of patients on therapy considering the skepticism around adult demand at launch.

在美國，我們的合作夥伴協和麒麟 (Kyowa Kirin) 正在領導 Crysvita 的商業化。2025 年第一季的收入得益於新開始表格的增加和報銷治療的新患者的增加。令人欣慰的是，考慮到剛推出時人們對成人需求的懷疑態度，大約有一半的成年人接受了治療——大約有一半的成年人接受了治療——已經超過了成人的需求。

We expect 2025 US pursuit of revenue to continue growing as they work to identify new pediatric and adult patients with XLH and convert them to treatment. Moving on to Dojolvi in the United States, growth of new start forms in the first quarter continued to steadily increase, just as we have seen in prior quarters. Our team generated approximately 30 new start forms and added approximately 25 new patients to reimbursed therapy. This brings the total since launch in 2020 to almost 600 patients on reimbursed therapy.

我們預計，隨著美國致力於發現新的 XLH 兒科和成人患者並對其進行治療，2025 年美國的收入將繼續增長。轉向美國的 Dojorvi，第一季新創公司數量繼續穩步增長，正如我們在前幾個季度看到的那樣。我們的團隊產生了大約 30 份新的開始表格，並為報銷治療增加了約 25 名新患者。這使得自 2020 年啟動以來接受報銷治療的患者總數達到近 600 名。

The split between pediatric and adult patients continues to be approximately 65% peds and 35% adults. Also, the number of new prescribers continue to grow in the first quarter with approximately 270 unique prescribers.

兒科患者與成人患者的比例仍約為 65% 為兒科患者，35% 為成人患者。此外，第一季新開處方者的數量持續增長，約 270 名新開處方者。

For Dojolvi across the EMEA region, there are over 260 patients treated under named patient sales across the region. The majority of demand is from France, but we are receiving an increasing number of requests from other countries within the EMEA region, including the Middle East. The demand for this product is quite strong in this region, especially given we are not actively marketing the therapy and simply responding to named patient requests.

對於 EMEA 地區的 Dojorvi 而言，該地區有超過 260 名患者透過指定患者銷售接受治療。大部分的需求來自法國，但我們收到來自 EMEA 地區其他國家（包括中東）越來越多的請求。該地區對該產品的需求相當強勁，特別是考慮到我們並沒有積極推銷這種療法，而只是響應指定患者的要求。

I'll close with a few comments on Evkeeza, which we began commercializing in our territories outside of the US in 2023. In the EMEA region, we have patients on reimbursed therapy from the majority of major countries. We now have treated approximately 250 patients, adding more than 50 since the beginning of the year across 15 countries in the region. This is the result of our commercialization efforts and response to named patient requests as we continue to successfully navigate the country-by-country pricing negotiations.

最後，我想對 Evkeeza 發表一些評論，我們在 2023 年開始在美國以外的地區對其進行商業化。在歐洲、中東和非洲地區，我們接受報銷治療的患者來自大多數主要國家。目前，我們已經為該地區 15 個國家的大約 250 名患者進行了治療，自今年年初以來又增加了 50 多名患者。這是我們商業化努力和回應指定患者要求的結果，我們繼續成功進行逐國定價談判。

In Japan, the team continues to build on the launch momentum following the pricing and reimbursement approval that we received last year. In Canada, we are continuing pricing negotiations with government health authorities and have secured reimbursement agreements with three of the four major private insurers.

在日本，繼去年獲得定價和報銷批准後，團隊繼續保持發布勢頭。在加拿大，我們正在繼續與政府衛生部門進行價格談判，並已與四大私人保險公司中的三家達成報銷協議。

Over time, we expect Evkeeza revenue to contribute more meaningfully to total revenue as we continue to successfully launch this important product outside of the United States. As I have mentioned on previous earnings calls, we continue to expect quarter to quarter variability in revenue, primarily due to uneven ordering patterns for Crysvita in LatAm. But we remain confident in the underlying demand for all of our products around the world.

隨著時間的推移，隨著我們繼續在美國以外成功推出這項重要產品，我們預計 Evkeeza 收入將對總收入做出更有意義的貢獻。正如我在之前的財報電話會議上提到的那樣，我們仍然預計收入將逐季度發生變化，這主要是由於 Crysvita 在拉丁美洲的訂購模式不均衡。但我們仍然對我們所有產品在世界各地潛在的需求充滿信心。

With that, I'll turn the call to Howard to share more details on our financial results and guidance.

說完這些，我將把電話轉給霍華德，讓他分享更多關於我們的財務表現和指導的細節。

Thanks, Erik, and good afternoon, everyone. I'll focus on first-quarter 2025 financial results and guidance for the year, starting with revenue. In the first quarter of 2025, we reported $139 million, representing 28 % growth over the first quarter of 2024. Crysvita contributed $103 million, including $41 million from North America, $55 million from Latin America and Turkey, and $7 million from Europe. In total, this represents 25% growth over 2024. If you focus on Latin America and Turkey, where we are responsible for generating sales, this represents 52% growth over 2024.

謝謝，埃里克，大家下午好。我將重點放在 2025 年第一季的財務表現和年度指導，首先是收入。2025 年第一季度，我們的營收為 1.39 億美元，比 2024 年第一季成長 28%。Crysvita 貢獻了 1.03 億美元，其中來自北美的 4,100 萬美元、來自拉丁美洲和土耳其的 5,500 萬美元、來自歐洲的 700 萬美元。總體而言，這意味著到 2024 年將成長 25%。如果您關注我們負責產生銷售額的拉丁美洲和土耳其，那麼這意味著到 2024 年銷售額將成長 52%。

Turning now to the Dojolvi, it contributed 17 million, consistent with its steady growth trajectory. Evkeeza contributed $11 million as demand continues to build following launches in our territories outside of the United States. And Mepsevii contributed $8 million as we continue to treat patients in this ultra-rare indication. Total operating expenses for the quarter were $282 million, which included R&D expenses of $166 million, SG&A expenses of $88 million, and cost of sales of $29 million. Operating expenses included non-cash, stock-based compensation of $40 million.

現在來看看 Dojorvi，它貢獻了 1700 萬，與其穩定的成長軌跡一致。隨著我們在美國以外地區推出產品後需求持續成長，Evkeeza 貢獻了 1,100 萬美元。Mepsevii 捐贈了 800 萬美元，用於繼續治療這種極為罕見的疾病患者。本季總營運費用為 2.82 億美元，其中包括研發費用 1.66 億美元、銷售、一般及行政費用 8,800 萬美元以及銷售成本 2,900 萬美元。營運費用包括 4000 萬美元的非現金股票薪酬。

For the quarter, net loss was $151 million, or $1.57 per share. As of March 31, we had $563 million in cash, cash equivalents, and marketable securities. which reflects $45 million in cash payments made for two milestones during the first quarter of 2025 that were achieved in the fourth quarter of 2024. Specifically, $30 million for a GTX102 Phase 3 study milestone and $15 million for an Evkeeza sales milestone.

本季淨虧損為 1.51 億美元，即每股 1.57 美元。截至 3 月 31 日，我們擁有 5.63 億美元的現金、現金等價物和有價證券。這反映了 2025 年第一季為兩個里程碑支付的 4,500 萬美元現金，這些里程碑已於 2024 年第四季實現。具體來說，GTX102 第三階段研究里程碑需要 3,000 萬美元，Evkeeza 銷售里程碑需要 1,500 萬美元。

In the first quarter of 2025, net cash used in operations was $166 million. Recall in the first quarter of the year, we typically use more operating cash than in the subsequent three quarters because it includes items like the payment of annual bonuses. In addition, first quarter net cash used in operations also included the $30 million GTX102 development milestone payment I mentioned earlier.

2025 年第一季度，經營活動所用淨現金為 1.66 億美元。回想一下，在一年的第一季度，我們通常會比接下來的三個季度使用更多的營運現金，因為其中包括支付年度獎金等項目。此外，第一季營運中使用的淨現金還包括我之前提到的 3,000 萬美元 GTX102 開發里程碑付款。

Net cash used in operations is expected to decrease in the remaining quarters of this year and is expected to total less than what we used in 2024, as we continue on our pathway to full year GAAP profitability in 2027.

隨著我們繼續朝著 2027 年全年 GAAP 盈利的目標邁進，今年剩餘幾季的營運淨現金使用量預計將會減少，預計總額將低於 2024 年的水平。

Shifting to revenue guidance for 2025, we are reaffirming the guidance we gave in February. Total revenue is expected to be between $640 million and $670 million, which represents 14% to 20 % growth over 2024. Drivers include increasing demand for our products in Latin America, continued penetration of the pediatric and adult XLH markets in the US, and growth from Evkeeza in Europe and Japan. Crysvita revenue is expected to be between $460 million and $480 million, which includes all regions and all forms of Crysvita revenue to Ultragenyx. This range represents 12% to 17 % growth over 2024.

轉向 2025 年的收入指導，我們重申我們在二月給予的指導。預計總收入將在 6.4 億美元至 6.7 億美元之間，比 2024 年增長 14% 至 20%。驅動因素包括拉丁美洲對我們產品的需求不斷增加、美國兒科和成人 XLH 市場的持續滲透以及 Evkeeza 在歐洲和日本的成長。Crysvita 的收入預計在 4.6 億美元至 4.8 億美元之間，其中包括所有地區和所有形式的 Crysvita 收入給 Ultragenyx。這一範圍代表 2024 年的成長率為 12% 至 17%。

The Dojolvi revenue is expected to be between 90 and 100 million, which represents 2% to 14% growth over 2024. As in prior years, our Dojolvi projections represent a blend of faster growth in countries where we commercialize and lower growth in countries where we respond to named patient requirements.

Dojorvi 的營收預計將在 9,000 萬至 1 億之間，比 2024 年成長 2% 至 14%。與前幾年一樣，我們的 Dojorvi 預測表明，在我們實現商業化的國家中，成長速度較快；在我們回應指定患者需求的國家中，成長速度較慢。

Lastly, with respect to tariffs, the landscape continues to evolve. We are actively monitoring and evaluating multiple potential scenarios. Based on what we see currently, we do not expect to have a material exposure for any of our products, including Crysvita.

最後，關於關稅，情況不斷變化。我們正在積極監測和評估多種潛在情況。根據我們目前的情況，我們預計我們的任何產品（包括 Crysvita）都不會受到重大影響。

With that, I'll turn the call to our CMO, Eric Crombez, who will provide an update on our key clinical data readouts expected this year.

接下來，我將把電話轉給我們的行銷長 Eric Crombez，他將提供有關我們今年預計的關鍵臨床數據讀數的最新資訊。

Thank you, Howard, and good afternoon, everyone. I'll provide some brief operational updates on our late stage programs and review our upcoming clinical milestones. Starting with the UX143 for the treatment of osteogenesis imperfecta, the Phase 3 ORBIT study continues to progress well, and as we noted earlier in the year, the safety profile is similar to what was observed in Phase 2.

謝謝你，霍華德，大家下午好。我將提供一些關於我們後期專案的簡要營運更新，並回顧我們即將到來的臨床里程碑。從用於治療成骨不全症的 UX143 開始，第 3 階段 ORBIT 研究繼續進展順利，正如我們今年早些時候指出的那樣，其安全性與第 2 階段觀察到的相似。

Based on the Phase 2 data we previously shared, we are confident that the study will show a clinically and statistically significant reduction in annualized fracture rate at either the second interim or final analysis.

根據我們先前分享的第二階段數據，我們相信，該研究將在第二次中期或最終分析中顯示出年骨折率在臨床和統計學上顯著降低。

The ORBIT and COSMIC studies will both have an interim analysis mid-year after all patients have been on therapy for at least 12 months. The data readouts will be led by ORBIT, meaning that if ORBIT clears the p-value threshold of less than .01, we will look to see if COSMIC has cleared the same p-value threshold of less than .01. If ORBIT progresses to full study completion in the fourth quarter of this year, COSMIC will also continue to a data readout to align with the ORBIT data readout without spending assets at this interim assessment.

所有患者接受治療至少 12 個月後，ORBIT 和 COSMIC 研究都將在年中進行中期分析。數據讀數將由 ORBIT 引導，這意味著如果 ORBIT 清除了小於 .01 的 p 值閾值，我們將查看 COSMIC 是否清除了小於 .01 的相同 p 值閾值。如果 ORBIT 在今年第四季度完成全面研究，COSMIC 還將繼續讀取數據，以與 ORBIT 數據讀數保持一致，而無需在本次中期評估中花費資產。

Moving to GTX101 (sic - "GTX102") for the treatment of Angelman syndrome, we have set an ambitious goal of enrolling a 120-patient pivotal study in less than one year. I'm proud to report that we are on track to achieve this goal and we are actively working with sites in the US, Europe, and Japan to enroll patients.

轉向 GTX101（原文如此 - “GTX102”）治療天使綜合徵，我們設定了一個雄心勃勃的目標，即在不到一年的時間內招募 120 名患者進行關鍵研究。我很自豪地報告，我們正在實現這一目標，我們正在積極與美國、歐洲和日本的研究中心合作招募患者。

We've also made progress finalizing the AURORA protocol, which will study younger and older patients and those with other mutations. We expect to take this protocol through the regulatory process and begin enrollment later this year.

我們在完成 AURORA 協議方面也取得了進展，該協議將研究年輕和年長患者以及患有其他突變的患者。我們期望該協議能夠通過監管流程並於今年稍後開始招生。

Next, DTX401 for the treatment of glycogen storage disease type Ia. In our press release today, we shared some of the additional crossover data that will be included in our BLA filing mid-year. During the crossover period, patients demonstrated even greater reductions in total daily cornstarch at their last visit compared to baseline in both the ongoing DTX401 group and the placebo crossover to DTX401 group. Patients in the DTX401 group demonstrated a 60% reduction in daily cornstarch at their last visit with a mean follow-up of 120 weeks. This is a substantial and continued reduction compared to the 41 % reduction in daily cornstarch observed at week 48.

接下來，DTX401用於治療Ia型肝醣累積病。在我們今天的新聞稿中，我們分享了一些將包含在年中 BLA 文件中的額外交叉數據。在交叉期間，無論是正在進行的 DTX401 組或安慰劑交叉至 DTX401 組的患者，在最後一次就診時，每日總玉米澱粉攝取量與基線相比都有更大幅度的減少。DTX401 組患者在上次就診時每日玉米澱粉攝取量減少了 60%，平均追蹤時間為 120 週。與第 48 週觀察到的每日玉米澱粉減少量 41% 相比，這是持續大幅的減少。

Patients in the placebo to DTX401 group demonstrated a similar 64% reduction in daily cornstarch at their last visit, where the mean duration on therapy with DTX401 was 69 weeks. Patients in both groups have demonstrated statistically and clinically meaningful reductions in daily cornstarch requirements, demonstrating continued benefit from this gene therapy over time. GTX401 also continues to demonstrate a consistent and acceptable safety profile with no new safety signals identified.

安慰劑組和 DTX401 組的患者在上次就診時也表現出每日玉米澱粉減少 64% 的現象，其中 DTX401 治療的平均持續時間為 69 週。兩組患者每日玉米澱粉需求量均有統計學和臨床意義的減少，顯示這種基因療法能持續帶來益處。GTX401 也繼續表現出一致且可接受的安全性，沒有發現新的安全性訊號。

The manufacturing process at our Bedford, Massachusetts facility is going well, and we recently successfully completed our process performance qualification run. While the [TUC] transfer from a CDMO to our facility was done quickly and efficiently, it did impact our BLA submission timing. We were able to capitalize on this opportunity to collect more clinical data resulting in an even stronger clinical and CMC following package that we will submit to the FDA mid-year.

我們位於馬薩諸塞州貝德福德工廠的生產過程進展順利，我們最近成功完成了製程性能驗證運行。雖然從 CDMO 到我們工廠的 [TUC] 轉移快速且有效率地完成，但它確實影響了我們的 BLA 提交時間。我們能夠利用這個機會收集更多的臨床數據，從而形成更強大的臨床和 CMC 追蹤方案，並將於年中提交給 FDA。

Finally, I'll touch on UX701 for the treatment of Wilson disease. As noted in our press release today, we have recently begun enrolling patients into a fourth dosing cohort at a dose of 4.0e13. These patients will receive a new immunomodulation regimen with rituximab and tacrolimus, in addition to the corticosteroid regimen used in the previous cohorts.

最後，我將談談用於治療威爾森氏症的 UX701。正如我們今天的新聞稿中所述，我們最近已開始招募患者進入第四個劑量組，劑量為 4.0e13。除了先前隊列中使用的皮質類固醇方案外，這些患者還將接受利妥昔單抗和他克莫司的新免疫調節方案。

We expect that the combination of enhanced immunomodulation regimen and a moderately higher dose could achieve the broad response needed to select a dose to take forward into the pivotal Stage 2 of this study. Also noted in our press release today, the pivotal stage two portion of the protocol was amended to a 52-week randomized, open-label active control design. The open-label design allows for patients and investigators to be more comfortable with this continuation of standard of care, consistent with their experience in our other metabolic gene therapy programs.

我們預計，增強免疫調節方案和適度增加劑量的組合可以實現所需的廣泛反應，從而選擇合適的劑量進入研究的關鍵第 2 階段。我們今天的新聞稿中還指出，該方案的關鍵第二階段部分已修改為 52 週隨機、開放標籤活性對照設計。開放標籤設計使患者和研究人員能夠更舒適地繼續這種標準治療，這與他們在我們其他代謝基因治療計畫中的經驗一致。

The Stage 2 primary endpoints are largely the same as before, but instead of comparisons to placebo, they are now compared to the active control arm. Specifically, we will be looking at the change in 24-hour urinary copper from baseline to week 52 and percent reduction in standard of care by week 52.

階段 2 的主要終點與之前大致相同，但現在不是與安慰劑進行比較，而是與活性對照組進行比較。具體來說，我們將觀察從基線到第 52 週的 24 小時尿銅變化以及第 52 週治療標準的降低百分比。

I'll now turn the call back to Emil to provide some closing remarks.

現在我將把電話轉回給艾米爾，讓他發表一些結束語。

Thank you, Eric. Over the first part of the year, we made tremendous progress to executing on all fronts. Patients involved UX143 for osteogenesis imperfecta studies have now been enrolled for at least 12 months, and this enables our teams to start the process of cleaning and locking the databases that will be shared with the data monitoring committee in the next few months.

謝謝你，埃里克。今年上半年，我們在各方面的執行都取得了巨大進展。參與 UX143 成骨不全症研究的患者目前已入組至少 12 個月，這使我們的團隊能夠開始清理和鎖定資料庫的過程，這些資料庫將在未來幾個月內與資料監測委員會共享。

The feedback we hear from investigators with patients in the Phase 2 portion of the ORBIT study gives us confidence the treatment effect with setrusumab in osteogenesis imperfecta is transformative for these patients.

我們從 ORBIT 研究第 2 階段患者研究人員那裡聽到的回饋讓我們相信，setrusumab 治療成骨不全症的效果對這些患者俱有變革性。

In closing, we expect 2025 to be the most productive year in our company's history, with the commercial organization generating $640 million $670 million in revenue, and the development organization managing one BLA under review, a second BLA submitted in the middle of year, and multiple Phase 3 studies and rolling or reading out data, we are in prime position to lead the future of rare disease medicine.

最後，我們預計 2025 年將成為我們公司歷史上最富有成效的一年，商業組織將創造 6.4 億美元至 6.7 億美元的收入，開發組織將管理一份正在審查的 BLA、年中提交的第二份 BLA 以及多個 3 期研究和滾動或讀取數據，我們處於引領罕見病醫學未來的有利位置。

With that, let's move on to your questions. Operator, please provide the Q&A instructions.

好了，讓我們繼續回答您的問題。接線員，請提供問答說明。

(Operator Instructions) Yaron Werber with TD. Cowen.

（操作員指示）Yaron Werber 與 TD。考恩。

Great. So thank you so much for taking my question, Emil. Not surprisingly, it's going to be about setrusumab on the second interim analysis and one in -- question in two parts. Maybe the first one, Emil, you've talked recently about dispersion in the study. And that's something that when we look at the prior data in the Phase 2, the dispersion is not really shown. We can tell there's variability in how many fractures patients have a baseline. So can you maybe explain to us what do you mean by dispersion and maybe why it's important?

偉大的。非常感謝您回答我的問題，艾米爾。毫不奇怪，第二次中期分析將涉及 setrusumab，並將問題分為兩部分。也許是第一個，埃米爾，您最近談到了研究中的分散性。當我們查看第二階段的先前數據時，這種分散並沒有真正顯現出來。我們可以知道有多少骨折患者的基線有差異。那麼，您能否向我們解釋一下分散的含義以及為什麼它重要？

And then secondly, when we look at the 67% fracture reduction, if I recall correctly, that was it around six to seven months. Can you give us a sense what it was saying when it was a 14 months, the latest cut was at ASBMR. Thank you.

其次，當我們看一下 67% 的骨折減少率時，如果我沒記錯的話，那大約是六到七個月的時間。您能否讓我們了解一下 14 個月以來 ASBMR 最新一次裁員的情況？謝謝。

Sure, Yaron, Thank you. So I don't know if I actually used the word dispersion because that's like a statistician's term. I usually mentioned variation, that there is a variation in the annualized fracture rate at baseline.

當然，Yaron，謝謝你。所以我不知道我是否真的使用了“分散”這個詞，因為這就像統計學家的術語。我通常會提到變化，即基線年化骨折率存在變化。

And we know we have people are going to have more than three fractures a year and a flat fracture rate greater than 3 and some less. So we stratify the trials that those with a greater than 3 would be stratified equally between the treatment and placebo group, as would the ones below that.

我們知道有些人每年會發生三次以上的骨折，有些人的骨折發生率固定在 3 次以上，有些人的骨折發生率低於 3 次。因此，我們將試驗分層，將大於 3 的試驗平均分為治療組和安慰劑組，低於 3 的試驗平均分為治療組和安慰劑組。

But how it's distributed can have some impact on the probability of success just because variation is what really affects p-values.

但它的分佈方式會對成功的機率產生一定的影響，因為變化才是真正影響 p 值的因素。

So we haven't talked to that distribution that are shown here, but there is a fairly wide range of fractures baseline.

因此，我們還沒有討論這裡顯示的分佈，但是裂縫基線的範圍相當廣泛。

Now the statistical method we're using, the negative binomial, will capture the AFRs at baseline as a co-variable, meaning we'll help correct for that in the way we analyze it, which help assure that doesn't have a substantial impact. We're also stratifying by age in the trial.

現在，我們使用的統計方法，即負二項式，將捕獲基線的 AFR 作為協變量，這意味著我們將在分析方式上幫助糾正它，這有助於確保它不會產生實質影響。我們在試驗中也根據年齡進行分層。

So we're doing a number of things to help reduce variation but there is a lot of variation in severity and fracture frequency. And we I think we've done what we can. But that might be one reason why you might not hit IE2.

因此，我們正在採取多種措施來幫助減少差異，但嚴重程度和骨折頻率仍有很大差異。我認為我們已經盡力了。但這可能是您不使用 IE2 的一個原因。

We think we have a good shot at hitting IE2. It's everything we know. But we are very strongly positive in the trial whether IE2 or the end is going to be successful.

我們認為我們很有機會衝擊 IE2。這就是我們所知道的一切。但我們對於 IE2 或最終版本的測試是否能夠成功充滿信心。

So let's talk about the fracture reduction. We announced Phase 2 data after six months or so and showed a 67% reduction with a p-value of 0.04. Then when we did the 14-month cut of the same 24 patients, we had the same 67% reduction in fracture frequency median and the p-value, though, was 0.0014.

那我們來談談骨折復位。我們在大約六個月後公佈了第二階段的數據，結果顯示減少了 67%，p 值為 0.04。然後，當我們對同樣的 24 名患者進行 14 個月的分組時，我們發現骨折頻率中位數同樣降低了 67%，而 p 值為 0.0014。

So you might be wondering, well, how is the number the same? I would look at this as think of it as a line of accumulated fractures. The accumulated fractures in one group is going up at a steep rate and the slope of the other line is only 67% less, right?

那你可能會想，數字怎麼會相同呢？我會把它看作是一條累積的裂縫線。一組中累積的裂縫正在急劇上升，而另一條線的斜率僅低 67%，對嗎？

So the two lines are running at apart from each other. If you cut those the two lines earlier, they’re not as far apart. But if you wait for those two lines to progress further, they’re further apart. The slopes are still 67%, the same treatment effect size, but the p-value is better.

因此這兩條線是相距很遠的。如果您早點切斷這兩條線，它們之間的距離就不會那麼遠了。但如果你等待這兩條線進一步發展，它們之間的距離就會變得更遠。斜率仍為 67%，治療效果大小相同，但 p 值較好。

So what’s happening at interim one is that they may not have separated far enough yet and it would only would have happened if we had a lot of fractures. But by the second time we'll have run longer that we should have much better separation. So from that analysis, it suggests that we we could hit IE2. It's a reasonable shot.

因此，在第一個階段發生的情況是，它們可能還沒有分離得足夠遠，而且只有當我們有大量裂縫時才會發生這種情況。但第二次我們跑得更久，分離效果就會好很多。因此，從該分析來看，我們可以達到 IE2。這是一個合理的鏡頭。

Now we did do an analysis of our Phase 2 data for those that have heard this from me. We did take the same data and analyze the patients as if their prior year was on placebo and compared to their current year on treatment.

現在，對於那些從我這裡聽說這件事的人來說，我們確實對第二階段的數據進行了分析。我們確實採用了相同的數據，並對患者進行了分析，就好像他們前一年服用了安慰劑，並與他們今年接受的治療進行了比較。

And with the negative binomial, you get the same mid-60%s reduction, all right, with a good p-value. So just to be clear, if you do it by the method we’re using in Phase 3, you get a very similar result. Just because some people wondered whether the different statistical approach would matter.

而使用負二項式，你可以得到相同的 60% 左右的減少量，並且具有良好的 p 值。所以需要明確的是，如果您按照我們在第 3 階段使用的方法進行操作，您將獲得非常相似的結果。只是因為有些人想知道不同的統計方法是否重要。

So variability is an issue. Dispersion or statistical version of it, we could go into. But I think the key thing I would say is that I think we have plenty of power to succeed in the study whether it’s IE2 or at the end.

因此，可變性是一個問題。我們可以深入研究它的分散性或統計版本。但我想說的關鍵是，我認為我們有足夠的力量在研究中取得成功，無論是 IE2 還是最終版本。

All right. Let's go on.

好的。我們繼續吧。

Tazeen Ahmad, Bank of America.

美國銀行的塔津·艾哈邁德（Tazeen Ahmad）。

Hi. Good afternoon. Thanks for taking my question. Emil, I also have a question on OI.

你好。午安.感謝您回答我的問題。埃米爾，我對 OI 也有一個問題。

But this would be if the study moves to a third interim read, what’s your view of the likelihood of success? You’ve talked now multiple times about confidence in the molecule overall and we would agree that the drug is active.

但如果研究進入第三次中期閱讀，您認為成功的可能性有多大？您現在已經多次談到對分子整體的信心，我們也同意該藥物是有效的。

But if the study moves to the third interim, what would be a reason to be concerned that it would not work at the third interim? Thanks.

但是，如果研究進入第三個中期，有什麼理由擔心它在第三個中期不會起作用呢？謝謝。

Right. Well, it won’t be -- the next assessment is the final assessment for the study and that p-value threshold will be 0.04. So it would be a lot easier to hit 0.04. So we think that we will hit one or the other based on our experience what we’ve seen. I don’t think we could miss the 0.04 at that point with 18 months of time.

正確的。嗯，不會的——下一次評估是該研究的最終評估，p 值閾值將是 0.04。因此達到 0.04 會容易得多。因此，我們認為，根據我們所見的經驗，我們將擊中其中一個。我認為，在 18 個月的時間裡，我們不可能錯過 0.04。

But as always in rare disease programs, the thing you always are battling against is variation -- variability in patients. But based on the profound difference in bone marrow density change that we see that happens within two to three months and the fracture rate effect happens within two to three months, we feel pretty good about IE2 hitting, but confident about overall the study hitting even at the end, if not at the IE2.

但正如罕見疾病計畫中常見的情況一樣，你始終要應付的是變異──患者的變異性。但是，基於我們看到的兩到三個月內發生的骨髓密度變化的巨大差異以及兩到三個月內發生的骨折率效應，我們對 IE2 的達到感到相當滿意，但對總體而言，即使不在 IE2，研究最終也會達到預期效果充滿信心。

So I can’t tell you a reason why, but variation is always a thing that can create complexities. But given that the patients -- the program is 159 patients, that’s a pretty large study. And we were -- the data we’re talking about before was 24.

所以我無法告訴你原因，但改變總是會產生複雜性。但考慮到該項目涉及的患者數量為 159 名，這是一項相當大的研究。我們之前討論的數據是 24。

So I think we’ve got a lot of power in there, but we’ve done everything we can to manage variations. So I feel good about we’ll hit it this year either at 0.01 or 0.04 after 18 months.

所以我認為我們擁有很大的權力，但我們已經盡一切努力管理變化。因此，我很有信心，18 個月後我們就能達到 0.01 或 0.04 的目標。

Gena Wang, Barclays.

巴克萊銀行的 Gena Wang。

Thank you for taking my questions. Maybe a little bit switch gear, little bit the non-fundamental questions. I think it was a recent CBAR nomination of Vinay Prasad. And I think there is a lot of uncertainties. We saw massive sell off in the biotech sector.

感謝您回答我的問題。也許有點轉換話題，有點非基本問題。我認為這是最近 CBAR 對 Vinay Prasad 的提名。我認為存在著許多不確定性。我們看到生物科技板塊出現大規模拋售。

And so Emil, I wanted to get your thoughts like where do you see that could be potential impact to specifically in the rare disease space? And how do you deal with or what will be the strategy you have dealing with this situation? I mean, there’s still open questions, a lot of uncertainties there.

所以埃米爾，我想聽聽你的想法，你認為這可能會對罕見疾病領域產生哪些潛在影響？您如何處理這種情況，或者您處理這種情況的策略是什麼？我的意思是，仍然存在一些懸而未決的問題，許多不確定性。

And my second question is also go back to the OI. I think a recent discussion we had, you did mention that like over maybe eighty percent of patients has a baseline bisphosphonate and then the washout period in the late enrollment period, you did skip the washout period.

我的第二個問題也是回到 OI。我認為在我們最近的討論中，您確實提到過，大約 80% 以上的患者都有基線雙磷酸鹽，然後在後期入組期間有洗脫期，而您確實跳過了洗脫期。

So would that be any concern regarding, say, the placebo factory picking up at some point? Would that have a delay rather than, say, twelve months? Would they need a little bit longer time so that we can see the placebo arm, the factory start to pick up?

那麼，這是否會引起關於安慰劑工廠在某個時候復甦的擔憂？這是否會延遲，而不是十二個月？他們是否需要更長一點的時間才能讓我們看到安慰劑組和工廠開始復甦？

Very good. So, the CBER appointment, we don’t think was a good choice as someone who has argued against accelerated approval for cancer programs or and that may be a concern. I think we’d have to anchor back to the fact that Carrie has been talking about the importance of rare disease approvals and thinking how to improve and accelerate the process or reduce the time of development.

非常好。因此，作為一個反對加速批准癌症計畫的人，我們認為 CBER 的任命不是一個好的選擇，這可能是一個令人擔憂的問題。我認為我們必須回顧這樣一個事實，Carrie 一直在談論罕見疾病審批的重要性，並思考如何改進和加速這一進程或縮短開發時間。

So we’ll have to anchor to that discussion and point he’s made and see what Forsyth does. I think for our own program, for UX111, we have lots of clinical data in the program.

因此，我們必須圍繞這一討論和他提出的觀點，看看福賽斯會怎麼做。我認為對於我們自己的程序，對於 UX111，我們在程序中擁有大量的臨床數據。

I’m less concerned about it because of the fact we have clinical data showing efficacy in addition to the biomarker data. And so I think for us right now, we’re not concerned. But I think for industry at large, it’d be important for accelerated approval to be available for a lot of the gene or cell therapies. And it would be important that Carrie’s public commitment to try to move these things forward. It’s something that, he follows through on.

我對此不太擔心，因為除了生物標記數據之外，我們還有顯示療效的臨床數據。所以我認為就我們目前而言，我們並不擔心。但我認為，對於整個產業來說，對許多基因或細胞療法進行加速審批非常重要。重要的是，凱莉要公開承諾推動這些事情向前發展。這是他要堅持的事。

How Prasad will do that, we don’t know. But I think the FDA is very important. The industry supports FDA and their mission and we just hope that they continue to make good decisions. On the second question, more than eighty percent to ninety percent or something like that were on bisphosphonates in the study, right? Correct.

我們不知道普拉薩德將如何做到這一點。但我認為 FDA 非常重要。該行業支持 FDA 及其使命，我們只是希望他們繼續做出正確的決定。關於第二個問題，研究中超過百分之八十到九十的人使用雙磷酸鹽，對嗎？正確的。

Yes. And the washout timeframe is in the one to two year period. So we’d expect the placebo patients to be have steadily declining frac bisphosphonates effect and therefore steadily potentially increasing fracture rate as their bone marrow densities decline.

是的。而清除期則為一至兩年。因此，我們預期安慰劑患者的雙磷酸鹽作用將穩定下降，因此隨著骨髓密度下降，骨折率可能會穩定增加。

But we don’t think that effect is really a meaningful effect compared to the dramatic effect on bone marrow density that’s going to happen with cetuximab, right? Where for the five to twelve group, we had a twenty nine percent increase.

但我們認為，與西妥昔單抗對骨髓密度的巨大影響相比，這種影響並不是真正有意義的影響，對嗎？對於五至十二歲的兒童組，我們的增幅為百分之二十九。

The bone marrow density improvement, the effect on the other groups will not be nearly so large. So what it would do is both groups would have a loss of bisphosphate effect over the period. But remember, setrusumab arm will also have some anti resorptive effect from the drug itself. So if anything, what this will do is increase the rate of separation as time goes on and improve the power of the study longer it goes.

骨髓密度的改善，對其他組別的影響不會那麼大。因此，其結果是，兩組都會在一段時間內失去雙磷酸鹽的作用。但請記住，setrusumab 組藥物本身也具有一些抗吸收作用。因此，如果有的話，這樣做會隨著時間的推移增加分離率，並提高研究的能力。

Do you have anything else to add to that?

您還有什麼要補充的嗎？

Just that we didn’t count on this. When we were designing the study and powering the study, we did not account for that effect. So in any sense, that could be considered an upside.

只是我們沒有考慮到這一點。當我們設計研究並進行研究時，我們沒有考慮到這種影響。所以無論從什麼意義上來說，這都可以被視為一種好處。

Yes. Very good. Thank you.

是的。非常好。謝謝。

Salveen Richter, Goldman Sachs.

薩爾文·里克特，高盛。

Hi, this is Lydia on for Salveen. Thanks so much for taking our questions and congrats on all the progress. Just maybe another one on cetrusumab. Could you just discuss how you plan to message the outcome of the interim to the Street and whether you intend to share any data with this update? Thank you very much.

大家好，我是 Salveen 的 Lydia。非常感謝您回答我們的問題，並祝賀我們取得的所有進展。也許只是另一個關於 cetrusumab 的例子。您能否討論一下您計劃如何向華爾街傳達臨時結果，以及您是否打算在這次更新中分享任何數據？非常感謝。

Yes. So when we the D&C has presented the information on ORBIT, if it’s positive, they’ll inform us and we will inform the Street of the results. If they inform us that the study needs to go to the end, we’ll also inform the Street that the study is continuing to the end.

是的。因此，當我們的 D&C 向 ORBIT 提交資訊時，如果結果是肯定的，他們會通知我們，我們也會將結果告知華爾街。如果他們通知我們研究需要結束，我們也會通知華爾街研究將持續到結束。

So if you haven’t heard from us because the decision hasn’t happened yet and a decision either is moving forward to the final assessment or it’s ending at the interim will be clear. We haven’t set what all the data that might be in or not in that release, but different from interim one, we are having to fully clean the database for a potential filing from that data set.

因此，如果您還沒有收到我們的回复，因為決定尚未做出，並且決定是繼續進行最終評估還是暫時結束，這將是明確的。我們還沒有確定該版本中可能包含或不包含的所有數據，但與臨時版本不同，我們必須徹底清理資料庫，以便從該資料集中進行潛在的歸檔。

So the time to data would be faster than we have said for the IE1 where we had only partial lock and we had to continue the trial. So it would be relatively soon we talk about data. Now if IE2 is positive, then the COSMIC study will be evaluated. If Orbit is negative, then we won’t unblind the COSMIC data and we’ll wait for both studies to go to the next assessment. Okay?

因此，取得資料的時間會比我們所謂的 IE1 更快，因為在 IE1 中我們只有部分鎖定，而且我們必須繼續試用。因此我們很快就會討論數據。現在，如果 IE2 為陽性，那麼將對 COSMIC 研究進行評估。如果 Orbit 的結果是負面的，那麼我們就不會揭開 COSMIC 數據的神秘面紗，而是等待兩項研究都進入下一次評估。好的？

Thanks so much.

非常感謝。

Anupam Rama, JPMorgan.

摩根大通的 Anupam Rama。

Hi, thanks for taking the question. This is actually Malcolm Kuno on for Anupam. So where are you on your enrollment curve for the Angelman program? And have you opened all of the global sites for the program yet? Well, I’ll ask Eric to comment on that.

你好，謝謝你回答這個問題。這實際上是 Malcolm Kuno 為 Anupam 表演的。那麼，您在 Angelman 計劃的招生曲線上處於什麼位置？您是否已經開放了該計劃的所有全球站點？好吧，我會請埃里克對此發表評論。

Eric Crombez, Chief Medical Officer, Ultragenyx: Yes. So like we’ve said, our plan is to fully enroll that study this year. We are committed to that. We have really prioritized that and leverage the experience we had with OI and really enrolling for us for rare disease a relatively large pivotal trial. So we certainly want to do this as quickly as possible.

Ultragenyx 首席醫療官 Eric Crombez：是的。所以就像我們所說的那樣，我們的計劃是今年全面開展這項研究。我們致力於此。我們確實優先考慮了這一點，並利用我們在 OI 方面的經驗，為我們招募罕見疾病的相對大型關鍵試驗。所以我們當然希望盡快完成此事。

Yes, our global sites are active and beginning to screen and dose patients.

是的，我們的全球站點已開始活躍並開始對患者進行篩檢和給藥。

So all sites are active.

因此所有站點都處於活躍狀態。

Excellent. Thank you.

出色的。謝謝。

Kristen Kluska, Cantor.

克里斯汀·克魯斯卡（Kristen Kluska），領唱。

Hi, good afternoon. You talk about potential variation factors. I wanted to see color about how you’re thinking about the age of the baseline. I know investors tend to focus a lot about the types of OI, but based on some of the BMD data, you’ve shown that the effects could be even superior the younger you treat. And I know the ORBIT trial has a range of about twenty years. So is there anything you’re able to share?

嗨，下午好。您談論的是潛在的變化因素。我想了解您如何看待基線的年齡。我知道投資者往往非常關注 OI 的類型，但根據一些 BMD 數據，您已經證明，治療越年輕，效果可能越好。我知道 ORBIT 試驗的時間範圍大約是二十年。那麼您能分享一些什麼嗎？

I don’t think we shared the exact enrollment, but the majority of patients are going to be pediatric and a relatively limited number of older patients. We’re including them in order to allow us to label for adults as well off that study if there’s any question. But the majority of the patients are going to be in the pediatric age range for the program. Is there anything else you think we could offer, Eric?

我認為我們沒有分享確切的入組人數，但大多數患者都是兒科患者，老年患者的數量相對有限。我們將它們納入其中，以便我們在有任何問題時也能為成年人提供標籤。但該計劃中的大多數患者年齡都屬於兒科範圍。艾瑞克，您認為我們還能提供什麼嗎？

No, I think that covers it.

不，我想這就涵蓋了。

Thanks. And then just to clarify, if IE2 is if it does hit the analysis, will you also be announcing the same day whether COSMIC was successful as well or will those updates be separate? Thank you, again.

謝謝。然後需要澄清的是，如果 IE2 確實達到了分析要求，您是否也會在同一天宣布 COSMIC 是否也成功，或者這些更新是否會分開？再次感謝您。

We haven’t said it depends. They’re not happening the reviews of both programs are not happening the same day. One will happen and then the other. So we haven’t said yet whether we’d have them both in the same day or not. We’d like to keep you guessing a little bit, right? Why make it too easy?

我們並沒有說這取決於情況。這兩個項目的審查不會在同一天進行。一件事發生後，另一件事也會發生。所以我們還沒有說我們是否會在同一天舉辦這兩場活動。我們想讓您稍微猜一下，對嗎？為什麼要讓它變得太簡單呢？

Yigal Nochomovitz, Citi.

花旗銀行的 Yigal Nochomovitz。

Hi, thanks. Have you commented at all on the distribution of the types for OI for one, three and four for the Phase 2 versus the ORBIT trial? And then also this is a very specific question, but what exactly is the tolerance on these p-values? I mean, we’re talking about some pretty small numbers here. So I mean, hypothetically, if it’s like 0.011 in on the second interim, is that a fail or a win?

你好，謝謝。您是否對第 2 階段與 ORBIT 試驗中一型、三型和四型 OI 類型的分佈情況做過任何評論？這也是一個很具體的問題，但是這些 p 值的容忍度到底是多少？我的意思是，我們在這裡討論的是一些非常小的數字。所以我的意思是，假設第二次中期誤差是 0.011，那是失敗還是成功？

It’s I mean, I would I think I know, but I’m not sure actually. So I was just curious if you could clarify that level of detail and whether you were ever told the p-value for the first one, the first interim? Thanks.

我的意思是，我認為我知道，但實際上我並不確定。所以我只是好奇您是否可以澄清這個細節層面，以及您是否被告知第一個、第一個中期的 p 值？謝謝。

So on the OI types, think we’ve disclosed before that in the Phase 2 study, were seven Type IIIs and IVs and 17 Type I. And then because the doctors were then impressed with the results, then they were interested in bringing in their more severe three and four patients. So we ended up with more Type 3s about half the patients are Type three and four approximately there in the study. So it’s definitely an increase in Type 3s and 4s in the Phase 3 study than they were in the Phase 2 study. All right.

關於 OI 類型，我們之前已經揭露過，在第二階段的研究中，有 7 例 III 型和 IV 型患者，以及 17 例 I 型患者。由於醫生對研究結果印象深刻，因此他們有興趣引入病情更嚴重的三型和四型患者。因此，我們最終發現更多的是 3 型患者，研究中大約有一半的患者屬於第 3 型和第 4 型。因此，第三階段研究中的 3 型和 4 型糖尿病患者數量肯定比第二階段研究中的 3 型和 4 型糖尿病患者數量增加。好的。

Now for tolerance, we haven’t set that like how many sig figs of significance. Honestly, I don’t have an answer for you. But I would say if it’s like 0.015 or 0.016, is not less than 0.01, right? So that would probably that would be considered a miss at this point, which means you could be very close to a very good result and still miss and go to the end of the year, is why we shouldn’t overreact if there was an issue. But so that’s the basic the tolerance question.

現在對於容忍度，我們還沒有設定多少個顯著性指標。說實話，我沒有答案給你。但我想說，如果它像 0.015 或 0.016，就不會小於 0.01，對嗎？所以這可能在此時被認為是一次失誤，這意味著你可能非常接近一個非常好的結果，但仍然會失誤並到年底，這就是為什麼如果出現問題我們不應該反應過度。但這就是基本的容忍度問題。

And then the last one was whether it was the p-value and the others we haven’t provided a p-value. We were not aware of the p-value nor provided one in the interim the first interim. We were just told that it was study was continuing and no result. So what we know from the prior analysis of Phase 2 though that the p-value was 0.014 at 14 months. So we think there’s a reasonable chance of hitting IE2, pretty good chance of hitting IE2 and a much better chance of hitting IE2 at the 0.01 threshold than there was at IE1 with 0.001.

最後一個問題是它是否有 p 值，對於其他問題我們還沒有提供 p 值。在第一個中期，我們不知道 p 值，也沒有提供 p 值。我們只是被告知研究仍在繼續，但還沒有結果。因此，我們從第 2 階段的先前分析中得知，14 個月時的 p 值為 0.014。因此，我們認為達到 IE2 的可能性相當大，達到 IE2 的可能性相當大，而且在 0.01 的閾值上達到 IE2 的可能性比在 IE1 的 0.001 的閾值上達到 IE2 的可能性要大得多。

All right. Thank you, Yigal.

好的。謝謝你，伊加爾。

Thanks.

謝謝。

Joseph Schwartz, Leerink.

約瑟夫·施瓦茨，Leerink。

Hey, all. This is Will on for Joe. Thanks for taking our question and congrats on the progress this quarter. So one for us on Angelman. Now with three ASOs that are in or nearing pivotal development, including the one from Roche that was recently revived, are you thinking about the evolution of this market?

嘿，大家好。這是威爾代替喬上場。感謝您回答我們的問題，並對本季的進展表示祝賀。因此，我們為 Angelman 獻上一篇。現在有三個 ASO 正處於或接近關鍵發展階段，包括最近恢復的羅氏 ASO，您是否考慮過這個市場的發展？

And do you see a room for multiple treatment options? And how do you think these assets can potentially further differentiate themselves? And how do you think patients are going to be making decisions from a clinical trial or commercial therapy perspective? Thank you.

您是否認為存在多種治療方案的空間？您認為這些資產如何能進一步實現差異化？您認為從臨床試驗或商業治療的角度來看患者將如何做出決定？謝謝。

Thank you. Well, we are not usually company working in competitive space with a lot of products in the same space. So this will be a new thing. Usually, we’re working on first ever treatments in our by ourselves. So it’s definitely a different space.

謝謝。嗯，我們通常不是在競爭激烈的領域工作的公司，也不會在同一領域推出很多產品。所以這將會是一件新鮮事。通常，我們會自行進行首次治療。所以這絕對是一個不同的空間。

I would say in the regard of these ASOs, the most potent and effective drug will be the one that will tend to dominate. But that doesn’t mean there might not be a place for other molecules in the space as well. I think they’re very similar in terms of them being intrathecally administered ASOs.

我想說，就這些 ASO 而言，最有力、最有效的藥物將會佔據主導地位。但這並不意味著空間中沒有其他分子的容身之處。我認為它們在鞘內注射 ASO 方面非常相似。

But I do believe our drug is the most potent and has shown that and I think we’ve shown the best long term data, continuous improvement over long periods of time that has been shown for the INS molecule. The Roche molecule is sort of coming back into development.

但我確實相信我們的藥物是最有效的，並且已經證明了這一點，我認為我們已經展示了最好的長期數據，即 INS 分子在長期內持續改善的結果。羅氏分子正重新進入開發階段。

I am not concerned about. I think that that drug is even less potent and has other questions marks. So if there’s more than one out there, I think it will depend on efficacy and what people can show. I do think that we have because we expanded our Phase 2 study and we have almost 70 patients on drug, that we’re going to have a pretty big body of kids have been on drug several years. I think how those kids are going to doing are going to be probably even more impactful than the Phase 3 study.

我並不關心。我認為該藥物的效力更低，並且還有其他疑問。因此，如果有多種方法，我認為這將取決於功效以及人們能夠展示什麼。我確實認為我們已經做到了，因為我們擴大了第二階段的研究，而且我們有近 70 名患者在服用該藥物，因此我們將有相當多的孩子已經服用該藥物好幾年了。我認為這些孩子的表現可能會比第三階段的研究更有影響力。

That will be what people want to see, what’s my future like for my kid, if I’m on this. And we know from some of the early patients on there, the first one that actually had words, she had a few words in the first year, but now she’s speaking a few dozen words and has continued to gain ground over time.

這就是人們想看到的，如果我參與其中，我的孩子的未來會是什麼樣的。我們從那裡的一些早期患者那裡了解到，第一個真正能說話的患者，在第一年她只說了幾句話，但現在她已經能說幾十個字了，而且隨著時間的推移，她的水平不斷提高。

So I think that experience will be really important. I do think we’re in the best position to be the leader in the ASO space. And my hope going down the road that the top three ASO treatments will be our first product, then our second improvement and then the third next gen that comes out. And because we intend to be the leaders in the arrangements.

所以我認為經驗非常重要。我確實認為我們最有能力成為 ASO 領域的領導者。我希望未來排名前三的 ASO 治療方法將成為我們的第一款產品，然後是我們的第二次改進，然後是第三代下一代產品。因為我們打算成為這些安排的領導者。

Liisa Bayko. Evercore ISI.

莉莎·巴伊科。Evercore ISI。

Hi, thanks for taking the question. I just wanted to clarify, sorry to ask so many questions on just cetrusumab. Can you give us a little greater sense on where you are in terms of timing, what happens from here to data?

你好，謝謝你回答這個問題。我只是想澄清一下，很抱歉就 cetrusumab 問了這麼多問題。您能否讓我們更詳細地了解時間方面的進展，以及從現在到數據方面發生了什麼？

And then I just wanted to understand follow-up on an earlier question. If the data reads a positive, do you say it’s positive and then take some time to analyze the data and come back to us with the data? Or is that all in one press release? Thanks.

然後我只是想了解之前問題的後續情況。如果數據顯示為陽性，您會說它是陽性，然後花一些時間分析數據並將數據傳回給我們嗎？或者說這一切都包含在一份新聞稿中？謝謝。

Yes. So on the timing of data, because I think people may some people have had an unrealistic expectation that you would clean, lock and analyze the data in a couple of weeks or something. But this is a international Phase 3 study, and this clean and lock is the entire data set, not just the primary endpoint, the whole thing, because if it’s positive, we need to go straight to preparing a BLA filing.

是的。因此，關於數據的時間，因為我認為人們可能有些人抱有不切實際的期望，認為你會在幾週內清理、鎖定和分析數據。但這是一項國際性的 3 期研究，這個清理和鎖定是整個資料集，而不僅僅是主要終點，而是整個過程，因為如果結果是正面的，我們需要直接準備 BLA 檔案。

So there’s normally takes a Phase 3 around eight weeks of an international study to clean and lock a database, plus there will be some time to analyze and have a DMC meet and disclose. So at the time we find the result, we will there’ll be a much shorter time than we had before in terms of seeing what the data are.

因此，第三階段的國際研究通常需要大約八週的時間來清理和鎖定資料庫，此外還需要一些時間進行分析並讓 DMC 開會並披露資訊。因此，當我們得到結果時，查看資料的時間會比以前短得多。

We haven’t yet precisely said whether we’ll disclose it together at once or whether it be an initial read and some further. So we’re going leave that open right now. But our expectation is that we’ll be it’ll be sooner to getting the top line data than it would have been in IE1 where we had some other questions. So hopefully that gives you an idea, Liisa, of how it’s going to flow. Okay.

我們尚未明確表示是否會立即披露這些信息，或者是否進行初步解讀並進一步披露。所以我們現在就不討論這個問題。但我們的期望是，我們將能夠比在 IE1 中更快獲得頂線數據，因為我們還有其他一些問題。所以希望這能給你一個想法，莉莎，關於它將如何流動。好的。

Okay. So what I don’t understand what took the IE1 a little bit longer, just to understand the differences there. That’s my final question. Thank you.

好的。所以我不明白為什麼 IE1 花了更長的時間，只是為了了解那裡的差異。這是我的最後一個問題。謝謝。

Yeah, what happened to IE1 is that even if the interim was positive, the regulatory authorities wanted to have the majority of patients have at least twelve months of data. So we would have had to keep running the study for a couple of months.

是的，IE1 的情況是，即使中期結果是正面的，監管機構也希望大多數患者至少擁有十二個月的數據。因此我們必須繼續進行這項研究幾個月。

In other words, if I want to hit, we’d say, oh, we’re far enough along. And so we would then continue collecting data for a couple of months till more than half the patients had twelve months of data. And then we would have started and we’ve been doing all the final visits and cleaning and locking at that time.

換句話說，如果我想擊球，我們會說，哦，我們已經走得足夠遠了。因此，我們會繼續收集幾個月的數據，直到超過一半的患者擁有十二個月的數據。然後我們就開始，那時我們會做所有的最後檢查、清潔和鎖定工作。

So there had been a delay before we clean and lock. So you wouldn’t be able to see the data for not just two months, but probably three to four months, because we have to clean and lock it. So the timeframe here is much faster because we’re going to clean lock the whole database this time and we would be able to release top line data sooner than we would have at IE1.

因此，在我們清理和鎖門之前，出現了一些延誤。因此，您不僅在兩個月內無法查看數據，而且可能在三到四個月內都無法查看數據，因為我們必須清理並鎖定它。因此這裡的時間框架要快得多，因為這次我們將徹底鎖定整個資料庫，並且我們能夠比 IE1 更快地發布頂線資料。

Luca Issi, RBC Capital.

伊西（Luca Issi），加拿大皇家銀行資本管理公司（RBC Capital）。

Great. Thanks so much for taking my question. Congrats on the progress. Maybe just one more on OI just to be super, super clear. In a scenario where you actually don’t hit the second interim look, will the DSMB share with you the p-value?

偉大的。非常感謝您回答我的問題。恭喜你取得進展。也許在 OI 上再多說一點，只是為了更清楚。在您實際上沒有進行第二次中期審查的情況下，DSMB 會與您分享 p 值嗎？

Just wondering whether you will have a sense of whether you missed by a narrow margin or not. And then maybe related, is it fair to assume that the PRV for OI is possible only if you hit in a second interim look? My understanding is that you need to get approved by the end of twenty twenty six in order to get the PRV given that there’s sunsetting that program. Any context there? Much appreciated. Thanks so much.

我只是想知道您是否知道自己是否以微弱差距錯過了勝利。然後也許相關的是，假設只有在第二次中期觀察時才有可能實現 OI 的 PRV，這公平嗎？我的理解是，由於該計劃即將終止，您需要在 2026 年底之前獲得批准才能獲得 PRV。有上下文嗎？非常感謝。非常感謝。

Yes. So if we don’t hit it, we’ll just find out that the study is continuing and we didn’t hit it. We will not get any p-values. We won’t know if it’s close. We do have PI3 designation and we’d have to get approved by October.

是的。所以如果我們沒有達到目標，我們會發現研究仍在繼續，而我們卻沒有達到目標。我們不會得到任何 p 值。我們不知道它是否接近了。我們確實擁有 PI3 稱號，並且必須在 10 月之前獲得批准。

So whatever timeframe we file would have to be within the timeframe to get approval by October. Obviously, I2, it’s easier. If we have to go to the end of the study, then the time to file would have to be much shorter and the review rapid. But I would also point out to you, we do have breakthrough therapy designation for this program. So I think there are reasons why we could be able to accelerate things if need be.

因此，無論我們提交什麼時間，都必須在十月之前獲得批准的時間範圍內。顯然，I2 更容易。如果我們必須完成研究，那麼提交的時間就必須更短，審查也必須更快。但我還要指出的是，我們確實為這個計畫獲得了突破性治療認證。因此我認為，如果需要的話，我們有理由加快進程。

But our goal would be to get this filed in time to get a third PRB. Short of that, we certainly have already potentially two PRBs in place if 111 gets approved for Sanfilippo and if DTX401 gets approved for GSDIa.

但我們的目標是及時提交申請以獲得第三個 PRB。除此之外，如果 111 獲得 Sanfilippo 的批准，而 DTX401 獲得 GSDIa 的批准，我們肯定已經有兩個 PRB 了。

So I don’t think there’s anyone with potentially three PRVs still in play without the reauthorization. I do believe the bill will get reauthorized. I think we’ve had the assurance of that is true, but I think right now there’s some of the other matters that are top of mind in Capitol Hill that that one will take a little while before it will come up.

因此，我認為，在沒有重新授權的情況下，不可能有人繼續持有三套 PRV。我確實相信該法案將獲得重新授權。我想我們已經確信這是真的，但我認為現在國會山莊還有一些其他問題需要解決，這些問題還需要一段時間才能解決。

To clarify that, the 143 is in October of 2026. We need approval by October 2026.

需要澄清的是，143 是在 2026 年 10 月。我們需要在 2026 年 10 月之前獲得批准。

Right. Next question. Thanks, operator.

正確的。下一個問題。謝謝，接線生。

Joon Lee, Truist Securities.

Joon Lee，Truist Securities。

Hello. Good afternoon and thanks for taking our question. This is Mehdi on for Joon. So I go on OI and follow-up Igor’s question on composition of OI types. So do you agree that setrusumab's MOA benefits the Type 1 patients more than Type 4 and 3? This is the question.

你好。下午好，感謝您回答我們的問題。這是 Mehdi 代替 Joon 上場的。因此我繼續討論 OI 並跟進 Igor 關於 OI 類型組成的問題。那麼您是否同意 setrusumab 的 MOA 對第 1 型患者的益處大於第 4 型和第 3 型患者？這就是問題所在。

Well, I know there’s been some academics saying that, but and I know some of them are very good academics, but they’re actually incorrect because we already have data. So it’s not the theory would be that in Type 1 patients here deficient in collagen, we don’t have abnormal collagen. Therefore, if we just make more bone, it’ll be okay. And the Type 3 and four have abnormal collagen and therefore it’s not improved. But that’s not actually what we saw.

嗯，我知道有些學者是這麼說的，而且我知道他們中的一些人是非常優秀的學者，但他們的觀點實際上是錯的，因為我們已經有數據了。因此，理論上來說，對於缺乏膠原蛋白的第 1 型糖尿病患者來說，他們體內並沒有異常的膠原蛋白。因此，只要我們製造更多的骨頭，就沒問題。而第 3 型和第 4 型糖尿病的膠原蛋白異常，因此無法改善。但事實上我們看到的並不是這樣。

We see both of them have improved reduction of fractures. And in fact, the ones fractures we did see were in type one patients, I think were some of the ones not type three to four. So the truth is all of them are improved because while one is a deficiency of collagen and one is abnormal collagen, whether deficient or abnormal, the net benefit of making more bone is bone greater bone strength and reduced fractures. So it actually works in all three.

我們看到他們兩人的骨折減少情況都有改善。事實上，我們看到的骨折確實發生在第一類患者身上，我認為有些患者並不屬於第三類或第四類。因此，事實是，所有這些問題都得到了改善，因為雖然一個是膠原蛋白缺乏，一個是膠原蛋白異常，但無論是缺乏還是異常，骨骼增多的淨效益是骨骼強度更高，骨折減少。所以它實際上在這三種情況下都有效。

And historical clinical view of OI is going to change because the truth is that even with abnormal collagen, the bones can be strengthened, we believe in these patients and that’s what we’ve seen and that’s in the data from Phase 2.

對成骨不全症的歷史臨床觀點將會改變，因為事實是，即使膠原蛋白異常，骨骼也可以得到強化，我們相信這些患者，這就是我們所看到的，也是從第二階段的數據中得到的。

And so we’re confident that the type will not matter. You get the same bone density effect and the strength improvement will be the same regardless of the collagen mutation.

因此我們相信類型並不重要。無論膠原蛋白突變如何，您都會獲得相同的骨密度效果，並且強度的提高也將是相同的。

Thank you very much.

非常感謝。

Maury Raycroft, Jefferies.

莫里‧雷克羅夫特（Maury Raycroft），傑富瑞集團（Jefferies）。

Hi. Congrats on the progress and thanks for taking my question. I’ll ask one on OI as well. Just, I guess based on what you know about the baseline characteristics and expectations for variation, can you provide any perspective on how you’re thinking about the range of effect sizes on AFR reduction that would be needed to succeed on the second interim?

你好。恭喜您取得進展並感謝您回答我的問題。我也會在 OI 上問一個。只是，我想，根據您對基準特徵和變化預期的了解，您能否提供任何觀點，說明您如何看待在第二次中期取得成功所需的 AFR 減少的效果大小範圍？

Yes. So we’ve had that question in various forms of it like what’s clinically meaningful for fracture reduction. I think for clinically meaningful, most people say at least 30%, 40% would be clinically meaningful. Diphosphates are probably 20% or less, so anything like 30%, 40% or better. We don’t have a sense now for sure what the power would tell us.

是的。因此，我們以各種形式提出這個問題，例如，對於骨折復位來說什麼具有臨床意義。我認為就臨床意義而言，大多數人認為至少 30%、40% 才具有臨床意義。二磷酸鹽可能為 20% 或更少，因此為 30%、40% 或更高。我們現在還不確定這種力量會告訴我們什麼。

As I said before, when the curves separate, they’re linear essentially. And so we saw them separate within two to three months of treatment, which means when they get to even just 9%, 10% improvement in bone density, there’s already a separation in fracture frequency. But after that, though, it appears relatively linear, which tells me then that the percent reduction on the slopes won’t really change that much over time.

正如我之前所說，當曲線分離時，它們本質上是線性的。因此，我們看到他們在治療後的兩到三個月內就分開了，這意味著當他們的骨密度僅提高 9% 或 10% 時，骨折頻率就已經分開了。但在那之後，它看起來相對線性，這告訴我斜率的減少百分比實際上不會隨著時間的推移而改變太多。

And therefore, I don’t think you can think about like when you hit will determine what percent reduction you get. I think you have to think of it more as a slope and the time is will just depend how far apart the two lines are, how much how many fractures accumulated in one arm versus the other to give you the power.

因此，我認為你不能考慮何時擊中將決定你獲得多少百分比的減少。我認為你必須把它想像成一個斜坡，時間只取決於兩條線之間的距離，以及一隻手臂與另一隻手臂中積累了多少骨折來給你力量。

Does that answer your question?

這回答了你的問題嗎？

Yes. I think so. It’s helpful. Thank you.

是的。我認為是的。這很有幫助。謝謝。

Laura Chico, Wedbush.

勞拉·奇科，韋德布希。

Hi. Thank you very much for taking the question. This is Dylan on for Lorie Chico. So for Crysvita, could you expand further on key growth drivers in the quarter? And maybe what is helping drive uptake more specifically in the LatAm and Turkey regions? Or I guess what is unique about patient identification efforts in these regions?

你好。非常感謝您回答這個問題。這是 Dylan 為 Lorie Chico 表演的。那麼對於 Crysvita，您能否進一步闡述本季的主要成長動力？也許什麼有助於推動拉丁美洲和土耳其地區的吸收？或者我猜想這些地區的病患辨識工作有何獨特之處？

Okay. Well, Crysvita is growing really well in Latin America, but I think it’s growing recognition of how much patients do. But I don’t know, Erik, if you had any thoughts on what you say about how wide it’s growing in Latin America particularly well?

好的。嗯，Crysvita 在拉丁美洲發展得很好，但我認為它越來越受到病人重視。但是，埃里克，我不知道您是否對您所說的它在拉丁美洲的發展範圍有什麼看法？

As I had stated in the opening remarks that patients are having a good experience with the product and physicians are now treating more and more of their patients to include adult patients in the LatAm region as well.

正如我在開場白中所說，患者對該產品的體驗良好，醫生現在正在治療越來越多的患者，包括拉丁美洲地區的成年患者。

o it’s a little bit about word-of-mouth and propagation of that through the public. We don’t have a particularly prominent patient diagnosis function in Latin America. There are certain doctors, I mean, employees that are doing patient fine, but it’s not quite the same because we don’t have the same tools in South America that we have in The US like we don’t have the codes, nine codes, 10 codes and other things to help us.

這有點像是口耳相傳和透過大眾傳播的方式。在拉丁美洲，我們沒有特別突出的患者診斷功能。我的意思是，有些醫生，有些員工對病人很好，但情況並不完全一樣，因為南美沒有和美國一樣的工具，例如我們沒有代碼、九碼、十碼和其他東西來幫助我們。

But yes, so it’s a little bit more word-of-mouth, but I think, it’s impressive, but I believe the sound feeling of doctors that this is transformative for patients means they’re just there. They want to get more and more on.

但是的，所以這更多的是口耳相傳，但我認為，這令人印象深刻，但我相信醫生們對這對患者來說是變革性的強烈感覺意味著他們就在那裡。他們想要獲得更多。

When I went down to the meeting last year, the Latin America Brazilian meeting on these patients, it was clear difference from the very first meeting we did at launch that every doctor had a story of how their kids were doing and we’re grateful, excited about it and we’re happy to be able to do something for these kids. So I think that mood is going to add the fact we’re getting adults on is great too, because we certainly had gotten more primarily peds on originally.

去年，當我參加拉丁美洲和巴西關於這些患者的會議時，與我們在啟動時舉行的第一次會議有明顯不同，每位醫生都有一個關於他們孩子狀況的故事，我們對此感到感激和興奮，我們很高興能夠為這些孩子做些事情。所以我認為這種情緒會增加我們讓成年人參與的事實也是件好事，因為我們最初主要關注的是兒科。

In addition to the strong demand for both pediatric patients and adult patients, As I stated there, we have now have reimbursement with the national authorities.

除了對兒科患者和成人患者的強烈需求外，正如我所說，我們現在已經與國家當局達成了報銷協議。

Yes, in Brazil. Brazil as well as in Mexico.

是的，在巴西。巴西和墨西哥。

Yes, that’s what’s really driven it for Brazil and Mexico driven a lot of the increase in uptake rather than just named patient approach. In Turkey, it’s still under named patient, but same things happen. Once the doctor starts treating people to see what happened, over a period of the year, they see how their bones doing, how the kids are doing, they get adamant about getting more kids on and parents or friends of people find out and that’s what a good drug will do. Even in an inpatient setting, people hear about a story and they all want to get something for their kids. So we’re excited about that continued growth of the product internationally.

是的，這才是真正推動巴西和墨西哥增加治療量的原因，而不僅僅是指定患者的方法。在土耳其，患者仍未被公開姓名，但同樣的事情發生了。一旦醫生開始治療患者，觀察一年中發生的情況，他們會觀察患者的骨骼狀況、孩子們的狀況，並堅持讓更多的孩子繼續接受治療，患者的父母或朋友也會發現這一點，這就是好藥的作用。即使在住院環境中，人們聽到一個故事後都想為自己的孩子買點東西。因此，我們對該產品在國際上的持續成長感到非常興奮。

And I think the investment in Latin America and the top tier team in Turkey have been rewarded by being able to build a really solid growing business for the company.

我認為，對拉丁美洲的投資和土耳其的頂級團隊已經獲得了回報，因為我們能夠為公司建立真正穩固的成長業務。

And I think that just sets us up well for when we bring setrusumab to the marketplace.

我認為這為我們把 setrusumab 推向市場做好了準備。

It will because I think there’s a lot to OI everywhere as well. Thank you for the question.

是的，因為我認為任何地方都有很多 OI 的機會。謝謝你的提問。

Jack Allen, Baird.

傑克艾倫，貝爾德。

Great. Thanks for taking the questions and congratulations on the progress made over the course of the quarter. One more logistical one on setrusumab. Have you pointed investors towards how many of the patients had 12 months of data at that first interim readout? It sounds like it was the minority of patients, but I’d love to hear if you’re willing to put a little bit more finer point on the percentage of patients.

偉大的。感謝您回答問題，並祝賀本季的進展。關於 setrusumab 的另一個後勤問題。您是否向投資人指出，在第一次中期讀數時有多少患者擁有 12 個月的數據？聽起來這只是少數患者，但如果您願意更詳細地說明患者的比例，我將非常高興。

And then also on setrusumab, I wanted to ask you about any disclosures you’ve made on the impact that setrusumab has had on bone pain. We recently did a call with a physician who mentioned bone pain is a key symptom for these OI patients, and I’d love to hear any impact setrusumab could have there. Thank you.

還有關於 setrusumab，我想問您是否披露過 setrusumab 對骨痛的影響。我們最近與一位醫生進行了通話，他提到骨痛是這些 OI 患者的主要症狀，我很想聽聽 setrusumab 對此可能產生的任何影響。謝謝。

Okay. I’ll talk a little about the IE1 and then maybe you can touch on the Impression Scale scores or just a little bit about pain, I guess. So just to understand the enrollment curve, we had a lot of patients enroll in the last two to three months of that trial, right? It was very much a hockey stick.

好的。我將稍微談論一下 IE1，然後你也許可以談談印象量表分數，或者只是稍微談論一下疼痛。因此，為了了解入組曲線，我們在該試驗的最後兩到三個月內有很多患者入組，對嗎？它看起來就像一根曲棍球棒。

So when we had -- the minimum was seven months at that time point, we had a lot of people who were at 8, 9, 10 months, right, and a relatively smaller number at the 12 to 17 month timeframe, relatively smaller tail, right? So the vast majority of patients had less than a year at that time.

所以當我們有 - 當時的最低限度是七個月時，我們有很多人處於 8、9、10 個月，對吧，而在 12 到 17 個月的時間範圍內，人數相對較少，尾巴相對較小，對吧？因此當時絕大多數患者的存活時間都不到一年。

In order to get the majority to have a year, you would take another two months or three months from when the cut was made. Does that make sense? So it’s a very steep accumulation at the end. A lot of the patients were less than a year then -- the majority were less than a year at the first interim.

為了讓大多數人有一年的時間，你需要從剪輯時起再花兩個月或三個月的時間。這樣有道理嗎？所以最終累積量非常大。當時，許多患者的年齡都不到一年──大多數患者的年齡在第一階段都不到一年。

So it will be a significant difference in the number of patients that have, let’s say, exposure beyond the two to three month period where they get the bone effect. So let’s talk about something other in fact. I think it’s actually really important. It’s true for Crysvita, too, that things other than the bones often are drivers. What’s our thought from what we’ve seen in the Phase 2 data, Eric?

因此，在接受超過兩到三個月的治療後，獲得骨骼效果的患者數量將有顯著差異。那麼事實上我們來談談其他的事情。我認為這確實非常重要。對 Crysvita 來說，也是如此，骨骼以外的因素也常常是驅動因素。艾瑞克，根據我們在第二階段的數據中看到的情況，我們的想法是什麼？

Yeah. No, agree. Pain is a big part of this and certainly very important to patients and important part of the evaluation for the clinical trial. So we are focused on pain, comfort, subscales, and really focusing more on type of assessments that you would do with sports physical functioning. We are also doing a traditional [SS36] to look at this, but definitely following pain over the long term.

是的。不，同意。疼痛是其中很重要的一部分，對病人來說當然非常重要，也是臨床試驗評估的重要部分。因此，我們關注的是疼痛、舒適度、分量表，並且更關注運動身體機能進行的評估類型。我們也在進行傳統的 [SS36] 來研究這個問題，但肯定會長期追蹤​​疼痛。

In Phase 2, we did hear a lot of improvement there. Anecdotally, we have heard that patients have had a lot of improvement in pain scores.

在第二階段，我們確實聽到了許多改進。據我們所知，患者的疼痛評分有了很大的改善。

Yeah. I would say to you based on how kids were feeling like they’re running, hey, I want to go to sports and stuff. They were feeling different, too. I mean, whether it’s pain or fatigue or generally malaise, these patients also got pretty energized, I think, right? And so that’s also what happened with Crysvita, by the way.

是的。根據孩子們跑步時的感覺，我會告訴你，嘿，我想去參加運動之類的活動。他們的感受也有所不同。我的意思是，無論是疼痛、疲勞或全身不適，這些病人也都變得精力充沛，我想，對吧？順便說一句，Crysvita 也遇到了同樣的情況。

That’s why Crysvita, the pickup was so fast. Kids feel good, parents see it. And I think that’s happening with OI, too. I think when your bones get stronger, even a little bit stronger, your body feels it and you know it. So we’re excited about it.

這就是為什麼 Crysvita 的提貨速度如此之快。孩子們感覺良好，父母也看得出來。我認為 OI 也會出現這種情況。我認為當你的骨骼變得更強壯，哪怕只是強壯一點點，你的身體就會感覺到，你也會知道。所以我們對此感到很興奮。

When we look at how many patients we have for that program and the fact that it’s more than even with XLH, it’s pretty clear that this program should exceed what we’ve done with Crysvita. And I think we’ll launch more rapidly. We just, of course, have to get our IE2 or a final data in hand and get to a file.

當我們看到該計畫的患者數量以及它比 XLH 患者數量還多這一事實時，很明顯，該計畫應該超過我們對 Crysvita 所做的努力。我認為我們會更快推出新產品。當然，我們只需要拿到我們的 IE2 或最終數據並獲取文件。

But we’re excited about the opportunity being larger than it is even with Crysvita. There’s very few times you get to do something amazing like that again and we’re really thankful to have an opportunity to take on a bone disease like osteogenesis imperfecta and turn it around for patients in the future. Thank you for the question.

但我們很高興看到，這個機會比 Crysvita 更大。能再次做出如此令人驚嘆的事情的機會非常少，我們非常感激有機會治療成骨不全症這樣的骨病，並在未來為患者扭轉這種狀況。謝謝你的提問。

Thank you. There are no further questions at this time. I’d like to hand the floor back over to Joshua Higa for any closing comments.

謝謝。目前沒有其他問題。我想將發言權交還給 Joshua Higa，請他發表最後評論。

Thank you. This concludes today’s call. If there are additional questions, please contact us by phone or at ir.ultragenyx.com. Thank you for joining us.

謝謝。今天的電話會議到此結束。如果還有其他問題，請透過電話或造訪 ir.ultragenyx.com 與我們聯絡。感謝您加入我們。

You may disconnect your lines at this time. Thank you for your participation.

現在您可以斷開線路。感謝您的參與。